Despite the importance of synaptic transmission in nervous system function, the mechanism of neurotransmitter release and the mechanisms of variable synaptic efficacy are poorly understood. The goals of the proposed research are (1) to determine and characterize the processes that are involved in transmitter release by developing a quantitative description of the effect of repetitive stimulation on transmitter release, (2) to investigate the mechanisms of the first component of facilitation, the second component of facilitation, augmentation, and potentiation (four processes that act to increase transmitter release) by looking for differential effects of external (Ca ions), (Sr ions), (Ba ions), (Mg ions), (Na ions), changes in osmolarity, and mitochondrial inhibitors on these four processes, and (3) to determine whether each one of the four processes, the first component of facilitation, the second component of facilitation, augmentation, and potentiation, is associated with a change in the statistical release parameters n and/or p from the quantal hypothesis of transmitter release (del Castillo & Katz, 1954, J. Physiol. 124, 560-573). Depending on the experiment, estimates of the relative amount of transmitter released at the vertebrate neuromuscular junction will be made from measurements of end-plate potentials recorded intracellularly or extracellularly or from measurements of end-plate currents recorded under voltage clamp. Models for the mechanism of transmitter release will be formulated and evaluated by comparing experimental results with predicted results obtained by simulation of the proposed mechanisms of release on a digital computer.